| Neuronal nitric oxide synthase protects against myocardial infarction-induced ventricular arrhythmia and mortality in mice. | |
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MedLine Citation:
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PMID: 19770398 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Neuronal nitric oxide synthase (nNOS) is expressed in cardiomyocytes and plays a role in regulating cardiac function and Ca2+ homeostasis. However, the role of nNOS in cardiac electrophysiology after myocardial infarction (MI) is unclear. We hypothesized that nNOS deficiency increases ventricular arrhythmia and mortality after MI. METHODS AND RESULTS: MI was induced in wild-type (WT) or nNOS(-/-) mice by ligation of the left coronary artery. Thirty-day mortality was significantly higher in nNOS(-/-) compared with WT mice. Additionally, nNOS(-/-) mice had impaired cardiac function 2 days after MI. Telemetric ECG monitoring showed that compared with WT, nNOS(-/-) mice had significantly more ventricular arrhythmias and were more likely to develop ventricular fibrillation after MI. Treatment with the L-type Ca2+ channel blocker verapamil reduced the incidence of arrhythmia and ventricular fibrillation in nNOS(-/-) mice after MI. To assess the role of nNOS in Ca2+ handling, patch-clamp and Ca2+ fluorescence techniques were used. Ca2+ transients and L-type Ca2+ currents were higher in nNOS(-/-) compared with WT cardiomyocytes. Additionally, nNOS(-/-) cardiomyocytes exhibited significantly higher systolic and diastolic Ca2+ over a range of pacing frequencies. Treatment with the NO donor S-nitroso N-acetyl-penicillamine decreased Ca2+ transients and L-type Ca2+ current in both nNOS(-/-) and WT cardiomyocytes. Furthermore, S-nitrosylation of Ca2+ handling proteins was significantly decreased in nNOS(-/-) myocardium after MI. CONCLUSIONS: Deficiency in nNOS increases ventricular arrhythmia and mortality after MI in mice. The antiarrhythmic effect of nNOS involves inhibition of L-type Ca2+ channel activity and regulation of Ca2+ handling proteins via S-nitrosylation. |
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Authors:
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Dylan E Burger; Xiangru Lu; Ming Lei; Fu-Li Xiang; Lamis Hammoud; Mao Jiang; Hao Wang; Douglas L Jones; Stephen M Sims; Qingping Feng |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-09-21 |
Journal Detail:
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Title: Circulation Volume: 120 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2009 Oct |
Date Detail:
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Created Date: 2009-10-06 Completed Date: 2009-10-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 1345-54 Citation Subset: AIM; IM |
Affiliation:
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Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada N6A5C1. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Arrhythmias, Cardiac / etiology*, mortality, prevention & control* Calcium / metabolism Calcium Channels, L-Type / physiology Coronary Vessels / pathology Electrocardiography Mice Mice, Inbred C57BL Mice, Knockout Monitoring, Physiologic Myocardial Infarction / complications*, prevention & control* Myocardial Ischemia / physiopathology Nitric Oxide Synthase Type I / deficiency, genetics, metabolism Superoxides / metabolism Telemetry Ventricular Dysfunction, Left / etiology |
| Chemical | |
Reg. No./Substance:
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0/Calcium Channels, L-Type; 11062-77-4/Superoxides; 7440-70-2/Calcium; EC 1.14.13.39/Nitric Oxide Synthase Type I |
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